Integrase Invasion: A Top HIV Clinical Development of 2013

By David Alain Wohl, M.D.

From TheBodyPRO.com

December 8, 2013

After a timorous start, our embrace of inhibitors of HIV-1 integrase has flowered into what promises to be a long-term love triangle among integrase inhibitors, the providers who prescribe them, and the patients who must swallow them. One look at the Oct. 30 update to the U.S. Department of Health and Human Services (HHS) guidelines is all it takes to see this integrase lovefest -- considering that more than half of the regimens listed as preferred for initial treatment, expanded from four to seven, are integrase inhibitor-based.

And, why not? Over the past decade, the number of new potent antiretroviral agents has grown; yet, patients preparing to start HIV therapy have still had to choose from a constricted list of imperfect options. Essentially, the selection of initial therapy came down to choosing between the fixed-dose formulation of efavirenz/tenofovir/emtricitabine (Atripla) and one of two flavors of ritonavir (Norvir)-boosted protease inhibitors (darunavir [Prezista] or atazanavir [Reyataz]) plus tenofovir/emtricitabine (Truvada).

When the efavirenz (Sustiva, Stocrin)-based single tablet became available in 2006, the troublesome neuropsychiatric adverse effects of the regimen seemed a relatively small price to pay for convenience and potency. But, do our patients really need to continue to have to deal with nighttime dosing, a break-in period of dream disturbance, and a nagging question of mood effects (see the next highlight)? Likewise, the boosted protease inhibitor regimens are excellent at suppressing viremia and are virtually bulletproof against drug resistance, yet require multiple pills, bottles, co-pays, plus are straddled with important potential drug-drug interactions.

Elvitegravir/cobicistat/emtricitabine/tenofovir -- in patients with an estimated CrCl ≥70 mL/min

Dolutegravir + abacavir/lamivudine -- in patients who are HLA-B*5701 negative

Dolutegravir + tenofovir/emtricitabine

Raltegravir (Isentress) plus tenofovir/emtricitabine offered an option that played well with other medications with almost non-existent toxicity. But, unlike the other first-line regimens, it requires twice-daily dosing -- an understandable deal-breaker for many people living with HIV who want to take as few pills as infrequently as possible over the course of their, now extended, lives.

This is why the release of elvitegravir and dolutegravir (Tivicay, DTG) are a big deal. The single-pill-a-day elvitegravir tablet is a marvel of medicinal chemistry and holds its own against alternatives, including efavirenz and ritonavir-boosted atazanavir. The cobicistat appears to be a hair better tolerated than low-dose ritonavir and may have less of an impact on lipids, particularly triglycerides. Dolutegravir is a stand-alone pill, but a small one at that, and will be co-formulated with abacavir/lamivudine (Epzicom, Kivexa) soon. It also has an impressive clinical trial track record against efavirenz- and raltegravir-based regimens, as well as ritonavir-boosted darunavir. Dolutegravir is also a switch-hitter in that it has been studied with both tenofovir/emtricitabine and abacavir/lamivudine.

The Bottom Line

These new integrase inhibitors do not smooth over every last rough edge of HIV therapy -- there are still some potential drug interaction issues, particularly with the cobicistat needed to boost elvitegravir, and resistance may be an issue for those with major adherence problems. There is also the small, but annoying, artifactual increase in serum creatinine caused by both cobicistat and dolutegravir, as these agents block transporters responsible for moving creatinine from the blood to the urine across the tubular membrane. The elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) tablet currently is indicated in those with an estimated glomerular filtration rate (eGFR) of 70 mL/min. Still, these inhibitors of integrase seem to offer us a bit of what we liked most in the older regimens: the simplicity of the fixed-dose NNRTI and a relatively decent barrier to resistance, albeit not as high as that of the boosted protease inhibitors.

Efavirenz- and ritonavir-boosted protease inhibitors have held a near monopoly on our attention and that is now over as we get to know (and perhaps love) this emerging class of antiretrovirals.

David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.

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